The long-term objective of this proposal is to understand how the immune and neuroendocrine systems interact when activated by an inflammatory stimulus. The Specific Aims will focus on the inflammatory cytokines and mechanisms of hypothalamic-pituitary-adrenal (HPA) activation, and on the modulation of cytokine and HPA responses to inflammation by leptin and the melanocortin system. There is evidence that leptin, which is synthesized by fat cells and plays a key role in regulating energy homeostasis, can also modulate the inflammatory response. Alpha-MSH which is derived from the proopiomelanocortin (POMC) precursor protein, is synthesized in the periphery and can be regulated by leptin. Alpha-MSH has potent anti-inflammatory properties and can antagonize many of the actions of the inflammatory cytokines. Little is known, however, about the role of the endogenous melanocortin system, consisting of alpha-MSH, the melanocortin receptors, and the MSH antagonist, agouti-related protein (AGRP), in modulating cytokine and neuroendocrine responses. This proposal will examine the role of leptin, alpha-MSH and AGRP in modulating pro-inflammatory (IL-1-beta, IL-6, TNF-alpha) and anti-inflammatory cytokine (1L-1-beta and IL-10) responses to endotoxin and IL-1-beta in the rhesus monkey. Major goals will be to determine the physiological roles that alpha-MSH and AGRP play both centrally and peripherally in modulating the HPA response to an inflammatory challenge and to determine if the effects of leptin on the HPA axis are mediated in part by alpha-MSH. A rodent model will be used to examine the effects of endotoxin on POMC and AGRP gene expression in the hypothalamus and to examine the effects of leptin on IL-1-beta stimulated CRH release from the hypothalamus in vitro. Mice which overexpress alpha-MSH and agouti protein will also be utilized to study the role of the melanocortin system and of leptin in modulating cytokine and neuroendocrine responses to endotoxin. Inflammatory cytokines have been implicated in a wide spectrum of human diseases ranging from infectious and autoimmune diseases to osteoporosis and cardiovascular disease. Within the brain, inflammatory cytokines have been implicated in neurodegenerative disease and illness-associated depression. An understanding of the endogenous hormonal mechanisms which regulate this inflammatory cytokine cascade is thus relevant to a broad range of human diseases [unreadable] [unreadable]